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2U11/12457U A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 13 October 2011 (13.10.2011) 2U11/12457U A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 9/00 (2006.01) A61K 47/18 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 9/70 (2006.01) A61K 47/20 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A61K 31/422 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, PCT/EP201 1/055271 KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (22) International Filing Date: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 5 April 201 1 (05.04.201 1) NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (25) Filing Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 10003705.0 6 April 2010 (06.04.2010) EP GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, (71) Applicant (for all designated States except US): TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, LABTEC GMBH [DE/DE]; RaiffeisenstraBe 4, 40764 EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Langenfeld (DE). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventors; and GW, ML, MR, NE, SN, TD, TG). (75) Inventors/ Applicants (for US only): BREITENBACH, Armin [DE/DE]; Widdauener Strasse 35, 51371 Lev- Published: erkusen (DE). SCHWIER, Nina [DE/DE]; Bahnstrasse — without international search report and to be republished 43, 415 15 Grevenbroich (DE). upon receipt of that report (Rule 48.2(g)) (74) Agents: VON RENESSE, Dorothea et al; Lohengrin- straBe 11, 40549 Dusseldorf (DE). < © o (54) Title: ORAL FILM FORMULATION (57) Abstract: Pharmaceutical composition comprising at least one triptan and at least one thiol-group containing reducing agent. "Oral film formulation" FIELD OF THE INVENTION The invention relates to an oral film formulation comprising an indole serotonin receptor antagonist (triptan), its production and use for the treatment of headache. BACKGROUND OF THE INVENTION Pharmaceutical dosage forms, such as orally dissolvable film formulations, which are dissolved rapidly in the mouth, are advantageous in a wide variety of aspects; in particular they facilitate the oral administration of medicaments to patients who have problems in swallowing or suffer from nausea or emesis. For these patients swallowing conventional oral administration forms such as film-coated tablets is often cumbersome. Due to the rapid disintegration of the film formulation within the buccal cavity the active ingredient from film formulation can be incorporated either over the oral or gastric mucosa. Accordingly these films can be designed to enable or support either gastrointestinal or buccal adsorption of the active ingredient. Headache is a common symptom of various conditions which all result in pain of the pain sensitive structures of the head. The World Health Organization (WHO) estimates that one adult in 20 has a headache every or nearly every day. The most relevant condition is migraine. Approximately 240 million people have migraine attacks each year, with women being affected three times more often than men. In addition, in developed countries, tension type or "stress" headaches are estimated to affect two- thirds of all adult males and over 80% of adult females. Headache disorders may impose substantial hardships and burdens on the afflicted individuals including personal suffering, impaired quality of life and high financial cost. Social activity and work capacity are reduced in almost all migraine sufferers and in 60% of tension headache sufferers. Finally, the long-term effort of coping with chronic headache disorders may also predispose the individual to other illnesses, such as depressions. Triptans which represent modified forms of serotonin (5- hydroxytryptamine; 5-HT), have been developed for the treatment of migraine headaches. Triptans are serotoninergic agents that exhibit receptor-selective properties. Although the principal mechanism of action of triptans is still under research, it is understood that they relieve various symptoms of a migraine headache by inhibiting the over activity of trigeminal nerve terminals through serotonin 5-HT1 B, 5-HT1 D, 5-HT1 F receptors that exist in blood vessels in the brain and trigeminal nerves. Furthermore they inhibit inflammation around blood vessels, hyperlucency and vasodilation. Triptans are currently regarded as the standard therapy of migraine. They are commercially available in various administration forms, such as e.g. the tablet Zomig- ZMT® comprising zolmitriptan. From WO 2008/040534 A2 non-mucoadhesive oral films with triptans are known. Oral triptan dosage forms are also disclosed in WO 2009/014960 A 1. It has now been found by the inventors of the present invention that within oral films the chemical stability of triptans often is unsatisfying. It particular it was observed that within oral films triptans to a certain extend degrade or metabolize to their N-oxide or other unwanted degradation products, which are pharmacologically ineffective. These degradation products or metabolites impede the quality of the triptan containing pharmaceutical composition. Thus, it is the objective of the present invention to provide a pharmaceutical composition containing a triptan, in particular a film formulation, wherein the triptan exhibits an increased chemical stability. SUMMARY OF THE INVENTION The invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of at least one triptan and at least one thiol-group containing reducing agent. This thiol-group containing reducing agent exhibits the function of an antioxidant agent, which stabilises the chemical integrity of the triptan. The pharmaceutical composition preferably is an oral film formulation. Accordingly the invention also relates to an oral film formulation, which comprises a pharmaceutically effective amount of at least one triptan, at least one film-forming polymer and at least one thiol-group containing reducing agent. The invention in particular relates to pharmaceutical compositions, e.g. oral film formulations, containing zolmitriptan. The invention is based on the finding that in the presence of at least one thiol-group containing reducing agent the chemical stability of the indole serotonin receptor agonist within a pharmaceutical composition is increased. This in particular applies when the indole serotonin receptor agonist is presented in an oral film formulation. With other words: At the presence of a thiol-group containing reducing agent the total amount of triptan degradation products or metabolites within the composition is reduced compare to compositions in absence of thiol-group containing reducing agent. In particular the total amount of the N-oxide of the respective triptan is reduced compared to an identical triptan containing pharmaceutical composition without a thiol-group containing agent. The N-oxide is a well known degradation product of triptans, which all are chemically characterised in containing an alylamino-group. The oxidation of this group results in the respective N-oxide. The N-oxide of zolmitriptan is known as "zolmitriptan N-oxide or (4S)-4-[[3-[2-(Dimethyloxidoamino)ethyl]-1 H-indol-5-yl]methyl-2-oxazolidinon (CAS No 251451-30-6). Accordingly the invention relates to a pharmaceutical composition comprising a stabilized triptan, e.g. stabilized zolmitriptan, namely to a composition wherein the zolmitriptan is stabilised with a thiol-group containing reducing agent against degradation into its N-oxid. The stabilising effect of the thiol-group containing agent does not only result in a reduced degradation of zolmitriptan into its N-oxid, but extends also to a so far unknown further degradation products, which the inventors designated "RTT 0.67" (according to its retention time in a chromatography). The invention furthermore relates to a method of stabilising triptans in a pharmaceutical composition and to the use of thio-group containing reducing agents for the stabilisation of triptans in pharmaceutical composition, in particular in pharmaceutical oral films. DEFINITIONS As used throughout the present application the following terms have the meaning indicated unless otherwise indicated: The term "disintegrate" as used herein is defined as in chapter 701 of the U.S. Pharmacopoeia (2005 USP/NF) for uncoated tablets, using a basket rack assembly operating at 30 cycles per minute through a distance of 5.5 cm, in a disintegration medium at 37°C. When disintegration requirements are discussed herein, they are preferably met under the foregoing testing conditions, at a pH of 4.0 or 6.8. A film or other dosage form is said to be "disintegrated" if it is completely disintegrated, a state in which any residue of the unit remaining on the screen of the test apparatus, or in the mouth, is a soft mass having no palpably film core, or fragments of a tablet coating or capsule shell. Disintegration thus does not require the complete dissolution of the dosage unit or the active agent, although a dissolved dosage unit would typically be completely disintegrated. "Thiol-group containing reducing agent" refers to a chemical substance that contains at least one -SH group (thiol group) and is able to reduce another species in a redox (reduction-oxidation) reaction. Examples include but are not limited to glutathione, cysteine, methionine, thioglycerol, thiogycol acid and others.
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